1. Field of the Invention
This invention relates to peptides that bind with high affinity and selectivity to the mu (morphine) opiate receptor; pharmaceutical preparations containing an effective amount of the peptides or salts thereof; and methods for providing analgesia, relief from gastrointestinal disorders such as diarrhea, and therapy for drug dependence containing an effective amount of the peptides.
2. Description of Related Art
Many peptides have been found that exhibit opiate-like activity by binding to opiate receptors. Three different types of opiate receptors have been found: delta (.delta.), kappa (.kappa.) and mu (.mu.). The major putative function for opiates is their role in alleviating pain. Other areas where opiates are well-suited for use in treatment are conditions relating to gastrointestinal disorders, schizophrenia, obesity, blood pressure, convulsions, and seizures. Although the .delta. and .kappa. receptors may also mediate analgesia, activation of .mu. receptors is the primary and most effective means of inducing analgesia, and is the primary mechanism by which morphine acts.
To date, opiates, opioid peptides, and analogs thereof, have demonstrated a limited degree of specificity and selectivity for the receptor or receptors to which they may bind. The less selective and specific an opiate may be, the greater the chance that increased side effects from the administration of the material will be observed. When an opiate activates more than one receptor, the biological response profile for each receptor is affected, thereby potentiating a spectrum of side effects which may or may not be adverse. Such adverse side effects include heaviness of the limbs, flush or pale complexion, clogged nasal and sinus passages, dizziness, and depression. Compounds that activate .kappa. receptors frequently induce dysphoria.
Peptides have been identified in mammalian brain that are considered endogenous agonists for .delta. (enkephalins) and .kappa. (dynorphins) opiate receptors, but none show clear preference for the .mu. receptor. Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH.sub.2) (SEQ ID NO:27) is an endogenous peptide isolated from human (1) and bovine (2) brain with opiate-related activity in the guinea pig ileum (1,2,3) and in tests of analgesia (4,5,6). It is highly selective for .mu. over .delta. and .kappa. receptors (&gt;200- and 300-fold), but its .mu. receptor affinity (Ki=70 nM) is relatively low (7). Numerous analogs have been made, most of which are based on modifications of the naturally occurring enkephalins that prefer the .delta. opiate receptor, or dynorphins that prefer the K receptor. In addition, most of these analogs are relatively hydrophilic, limiting their access to the central nervous system.
Because morphine and other compounds with clinical usefulness act primarily at the .mu. receptor, endogenous peptides with high affinity and selectivity for this site would be of considerable importance. These peptides, and analogs based on such peptides, that have a natural selectivity for the .mu. receptor would be advantageous for activating the .mu. receptor. It would also be desirable to synthesize these peptides in a simple, efficient, and economical manner to facilitate the preparation of suitable quantities for toxicological studies and commercial suppliers while retaining the optical integrity of the desired materials.